Early onset type 2 diabetes mellitus: a harbinger for complications in later years--clinical observation from a secondary care cohort.

BACKGROUND: Little is known about the complication burden in later years among early onset type 2 diabetes mellitus (T2DM). AIM: To determine the magnitude of diabetes complications and adequacy of risk factor management and to test the hypothesis that diabetes duration is an important contributing factor to these complications. DESIGN: A cross-sectional study of secondary care diabetes population. METHODS: Data on glycaemic control, cardiovascular risk factors (overweight/obesity, hypertension, dyslipidaemia), cardiovascular disease (CVD) and microvascular complications among those diagnosed before (early onset) and after (later onset) 40 years of age at different diabetes durations (<10, 10-20 and >20 years) were analysed. RESULTS: A total of 2733 subjects were identified, of which 527 had diabetes diagnosed below the age of 40 years. By the sixth decade of life, early onset cohort experienced high complication burden (CVD: 37.2%, retinopathy: 59.3% and neuropathy: 53.1%). Complication prevalence increased with diabetes duration but the increment rate was greater among early onset cohort. Compared with those diagnosed after 40, early onset cohort experienced similar burden of microvascular complications approximately 13-20 years earlier. Diabetes duration was a significant predictor for microvascular and CVD complications. Prevalence of CVD risk factors was high ( approximately 80-93%) regardless of the age of diagnosis and diabetes duration. Early onset subjects were more likely to have poorer glucose control ( approximately 70-78%), untreated hypertension (26.3%) and a substantial number did not receive statin treatment for primary prevention (34.8%). DISCUSSION: Early onset T2DM subjects are at substantial risk of developing diabetes complications in later years but at an earlier stage than later onset cohort and prolonged exposure to adverse diabetic milieu is an important contributing factor. Management of risk factors for diabetes complications was inadequate among early onset subjects.

Type 2 diabetes mellitus: a high-risk condition for cardiovascular disease irrespective of the different degrees of obesity.

BACKGROUND: Measurement of body weight with body mass index (BMI) is often utilized to stratify cardiovascular disease (CVD) risk. AIM: To determine CVD risk profile and disease burden in subjects with type 2 diabetes mellitus (T2DM) across different categories of body weight as defined by BMI. DESIGN: Prospective observational study. METHODS: CVD risk including metabolic syndrome (MetS) and prevalence of macrovascular complications were determined for each category of body weight as defined by the World Health Organisation (WHO) classification. RESULTS: A total of 390 subjects were included in this study of which 35.9% were non-obese (BMI <30 kg/m(2)). Although increasing obesity as defined by BMI was associated with higher prevalence of central abdominal obesity, hypertension and MetS (P < 0.05), dyslipidaemia and macrovascular complications were not significantly different across the various body weight categories (P = NS). Similar observation was seen in non-obese (BMI <30 kg/m(2)) and obese subjects (BMI >30 kg/m(2)). Among non-obese (including normal weight) cohort, the majority of these subjects had adverse CVD risk profile including presence of at least two co-existing risk factors. CONCLUSION: Subjects with T2DM possess adverse CVD risk factors with significant burden of macrovascular disease irrespective of their baseline body weight.

Diagnosing metabolic syndrome in type 2 diabetes: does it matter?

BACKGROUND: Metabolic syndrome (MetS) is used as a clinical tool to identify individuals at risk of cardiovascular disease (CVD) but its clinical value in the management of type 2 diabetes mellitus (T2DM) remains uncertain. AIM: To determine the prevalence and clinical usefulness of MetS among patients with T2DM attending diabetes clinics in a large teaching hospital. DESIGN: Prospective observational study. METHODS: Prevalence of MetS was determined by using International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) definitions in relation to age, sex, diabetes duration and history of CVD. RESULTS: A total of 390 patients were included in this study. Both IDF and NCEP-ATPIII definitions identified high prevalence of MetS in male and female patients (IDF: male vs. female, 91.7 vs. 94.8% and NCEP-ATPIII: male vs. female, 87.6 vs. 94.2%) regardless of age (below vs. above 40 yrs, approximately 70-75 vs. approximately 90-95% with both definitions), diabetes duration (below vs. above 5 yrs, approximately 85-90 vs. 90-95% with both definitions) and history of CVD (without vs. with CVD, approximately 90 vs. approximately 95% with both definitions). Central obesity was common reflected by mean waist circumference of approximately 113 cm regardless of age and gender. Among those who did not have IDF-defined MetS, approximately 60% had at least two CVD risk factors. Both definitions similarly classified approximately 94% of the patients as either having or not having MetS. DISCUSSION: Both definitions can be used interchangeably to diagnose MetS. However, the clinical usefulness of MetS is debatable given the very high prevalence of this condition in T2DM.

Chromium homeostasis in patients with type II (NIDDM) diabetes.

The purpose of this study was to assess chromium handling in non-insulin dependent diabetic patients (NIDDM) compared to healthy volunteers. Chromium handling was evaluated using fasting blood and second morning void urine samples from 93 NIDDM patients and 33 healthy volunteers. Significant differences in chromium homeostasis were seen between patients and controls. NIDDM patients had mean levels of plasma chromium around 33% lower and urine values almost 100% higher than those found in health. Healthy volunteers showed a significant negative correlation between fasting levels of plasma chromium and insulin. This was not evident in NIDDM patients. In the early years of onset of NIDDM, plasma chromium values were inversely correlated with plasma glucose. This was lost in patients with diabetes of more than 2 years duration. We suggest large losses of chromium over many years may exacerbate an already compromised chromium status in NIDDM patients and might contribute to the developing insulin resistance seen in patients with type 2 diabetes.

Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM.

OBJECTIVE: To assess the effects of short-term antecedent hypoglycemia on responses to further hypoglycemia 2 days later in patients with IDDM. RESEARCH DESIGN AND METHODS: We studied eight type I diabetic patients without hypoglycemia unawareness or autonomic neuropathy during two periods at least 4 weeks apart. On day 1, 2 h of either clamped hyperinsulinemic (60 mU.m-2.min-1) hypoglycemia at 2.8 mmol/l or euglycemia at 5.0 mmol/l were induced. Hyperinsulinemic hypoglycemia was induced 2 days later with 40 min glucose steps of 5.0, 4.0, 3.5, 3.0, and 2.5 mmol/l. Catecholamine levels and symptomatic and physiological responses were measured every 10-20 min. RESULTS: When compared with the responses measured following euglycemia, the responses of norepinephrine 2 days after hypoglycemia were reduced (peak, 1.4 +/- 0.4 [mean +/- SE] vs.1.0 +/- 0.3 nmol/l [P < 0.05]; threshold, 3.4 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l glucose [P < 0.01]). The responses of epinephrine (peak, 4.0 +/- 1.4 vs. 3.5 +/- 0.8 nmol/l [P = 0.84]; threshold, 3.8 +/- 0.1 vs. 3.6 +/- 0.1 mmol/l glucose [P = 0.38]), water loss (peak, 194 +/- 34 vs. 179 +/- 47 g-1.m-2.h-1 [P = 0.73]; threshold, 2.9 +/- 0.2 vs. 2.9 +/- 0.2 mmol/l glucose [P = 0.90]), tremor (peak, 0.28 +/- 0.05 vs. 0.37 +/- 0.06 root mean square volts (RMS V) [P = 0.19]; threshold, 3.2 +/- 0.2 vs. 3.1 +/- 0.2 mmol/l glucose [P = 0.70]), total symptom scores (peak, 10.6 +/- 2.1 vs. 10.8 +/- 1.9 [P = 0.95]; threshold, 3.3 +/- 0.2 vs. 3.6 +/0 0.1 mmol/l glucose [P = 0.15]), and cognitive function (four-choice reaction time: threshold, 2.9 +/- 0.2 vs. 3.0 +/- 0.2 mmol/l glucose [P = 0.69]) were unaffected. CONCLUSIONS: The effect on hypoglycemic physiological responses of 2 h of experimental hypoglycemia lasts for 1-2 days in these patients with IDDM . The pathophysiological effect of antecedent hypoglycemia may be of shorter duration in IDDM patients, compared with nondiabetic subjects.

Further evidence for a high incidence of nocturnal hypoglycaemia in IDDM: no effect of dose for dose transfer between human and porcine insulins.

We tested the hypothesis that transfer from porcine to human insulin causes a fall in nocturnal blood glucose and an increase in the frequency of hypoglycaemic episodes. Twenty IDDM patients (age 19-55, duration 3-36 years) used Velosulin and Insulatard twice daily for 12 weeks, double-blinded to species (human (H) or porcine (P)) in a randomized crossover study. Species was changed after 4 weeks' run-in and 4 weeks later, with insulin doses unchanged on transfer. Ten patients underwent each sequence (H/P/H or P/H/P) and were admitted on the first and eighth night after transfer for hourly blood glucose measurement (22.00-07.00). Biochemical hypoglycaemia (<3.5 mmol l(-1)) was observed on 39 of the 80 patient-nights studied (48.75%). The number of episodes were similar during each night (H1 8, H8 10, P1 10, P8 11, p = 0.83). Total reported symptomatic episodes (H 51 vs P 73, p = 0.85), total HbA1 (H 9.8 +/- 0.3%, P 10.0 +/- 0.3%, p = 0.32) and daily insulin doses (H 0.63 +/- 0.04 units kg(-1) day(-1) vs P 0.63 +/- 0.05 units kg(-1) day(-1), p = 0.54) were not different. Despite an apparent fall in blood glucose levels from night 1 to 8 on transfer to human (AUC 82.3 +/- 7.8 vs 61.4 +/- 5.3 mmol.h l(-1), p < 0.05) but not porcine insulin (AUC 70.7 +/- 7.2 vs 70.1 +/- 7.5 mmol.h l(-1), p = 0.74), there was no difference when all 4 nights were considered together (p = 0.30). We conclude that dose for dose transfer to human insulin does not increase numbers of episodes of nocturnal or reported hypoglycaemia.

Analysis of antibodies against components of the autonomic nervous system in diabetes mellitus.

Antibodies to autonomic nervous system structures have previously been detected using a complement fixation immunofluorescence test in the sera of patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM). These antibodies might play a role in the aetiology of autonomic neuropathy. Sera from 45 IDDM, 40 NIDDM and 52 control subjects were tested by immunofluorescence for antibodies to human sympathetic ganglia, human adrenal medulla and rabbit vagus nerve. The use of human sympathetic ganglia was compared with rabbit tissue for the detection of sympathetic ganglia antibodies; the results for these autonomic nervous system antibodies were also compared with results using an ELISA. There was no relationship between the presence of antibodies detected by ELISA and those detected by immunofluorescence, but of 14 IDDM patients with thyroid antibodies, 12 had autonomic nervous system antibodies detected by either immunofluorescence or ELISA (p < 0.005 compared to patients without thyroid antibodies). To further characterize the autoantigen(s), immunoblotting was performed. An adrenal antigen corresponding to 74 kDa was detected in sera from three patients, only one of whom had antibodies detectable by ELISA and immunofluorescence. One IDDM serum showed specific binding to a vagus nerve antigen corresponding to 33 kDa. No specific binding to sympathetic ganglia antigen was demonstrated. Antibodies against autonomic nervous system antigens are an inconsistent feature of diabetes, and appear more associated with coincidental autoimmunity against other organs such as the thyroid.

Similar physiological and symptomatic responses to sulphonylurea and insulin induced hypoglycaemia in normal subjects.

There is little information concerning the physiological response to hypoglycaemia induced by sulphonylureas. We compared the physiological and symptomatic responses to insulin and tolbutamide induced hypoglycaemia in 8 normal subjects. While infusing either insulin or tolbutamide, we used a glucose clamp to maintain blood glucose at 4.5 mmol l-1 for 30 min and lowered it to 2.9 mmol l-1 for a further 30 min. Mean peripheral insulin levels during the insulin infusion arm in comparison with the tolbutamide infusion were not significantly different during the euglycaemic plateau: 106 +/- 4 vs 77 +/- 15 mU l-1 (mean +/- SEM) (mean difference 29 mU l-1, 95% CI -22 to 80; p = NS) but were greater during the hypoglycaemic plateau: 106 +/- 3.5 vs 21.0 +/- 4.0 mU l-1 (mean difference 85 mU l-1, 95% CI 72 to 98; p < 0.0001). Portal insulin concentrations, calculated from C-peptide data were not significantly different during the euglycaemic plateau with insulin as compared to tolbutamide. However, during hypoglycaemia portal insulin concentrations were significantly higher 15 min from the start of the plateau, during insulin infusion. During hypoglycaemia induced by either insulin or tolbutamide there were similar peak responses of glucagon: 124 +/- 14 vs 128 +/- 7 ng l-1 (mean difference -4, 95% CI -39 to 31; p = NS) and adrenaline: 2.9 +/- 0.4 vs 2.8 +/- 0.3 nmol l-1, (mean difference 0.1, 95% CI -0.9 to 1.0; p = NS). Increases in tremor and sweating and deterioration in reaction time were similar during both periods of hypoglycaemia as were increases in total: 18.5 +/- 1.4 vs 19.6 +/- 2.2 (mean difference -1.0, 95% CI -3.8 to 1.8; p = NS) and autonomic: 8.9 +/- 0.9 vs. 9.9 +/- 1.3 (mean difference -1.1, 95% CI -5.9 to 3.6; p = NS) symptom scores. We conclude that there is no difference in the glucagon, sympathoadrenal, cognitive or symptomatic response during hypoglycaemia induced by either insulin or tolbutamide. This suggests that the different insulin concentrations produced by these contrasting models of hypoglycaemia had no effect on the physiological response and patients taking sulphonylureas can be expected to develop similar warning symptoms to those on insulin.

Prolonged but partial impairment of the hypoglycaemic physiological response following short-term hypoglycaemia in normal subjects.

Recent studies have reported reduced endocrine and symptomatic responses to hypoglycaemia 18-24 h after antecedent hypoglycaemia in both non-diabetic subjects and those with insulin-dependent diabetes mellitus. We examined these and peripheral physiological responses in eight non-diabetic subjects aged 23-35 years in the week following antecedent hypoglycaemia. Blood glucose levels were held at plateaus of 5 mmol/l and 2.5 mmol/l for 30 min during hyperinsulinaemic (60 mU x m-2x min-1) morning clamps on days 1, 3 and 8 of two study periods separated by at least 4 weeks. Measurements were made at time 0, 15 and 30 min of each plateau on each day. One the afternoon of Day 1 we also induced either euglycaemia with a blood glucose level of 5 mmol/l (control week) or hypoglycaemia of 2.9 mmol/l (hypo week) for 2 h in random order. The adrenaline response to morning hypoglycaemia (p<0.001 on all days) was attenuated on Day 3 (p<0.05) and Day 8 (p<0.05) compared to Day 1 of hypo week only. Sweating was also attenuated on Day 3 (p<0.05) and Day 8 (p<0.02) of hypo week only. Noradrenaline levels and tremor increased during hypoglycaemia on each study day (p<0.05) but did not differ between days in either week. During hypo week only, the total symptom score response to hypoglycaemia was attenuated on Day 3 (p<0.03) but not Day 8 (p=0.10). Autonomic symptoms were similarly affected. In summary, the physiological responses to hypoglycaemia are affected differentially by antecedent hypoglycaemia with sweating and adrenaline responses remaining impaired for at least adrenaline responses remaining impaired for at least 5 days.

Impotence in diabetes: aetiology, implications for treatment and preferred vacuum device.

In an assessment of the contributions of autonomic neuropathy and vascular disease to the aetiology of male impotence in diabetes, evidence of autonomic neuropathy was identified in 23/39 (59%) individuals complaining of impotence. Thirteen of 26 men aged < 60 years tested with an intracorporeal injection of papaverine experienced little or no response and seven had tumescence but no rigidity. Radioisotope phallography demonstrated vascular disease in six of these seven, suggesting evidence of a vascular component in 19/26 (73%). Only one patient had non-organic impotence. Overall, evidence of vascular disease alone was demonstrated in 10/26 (38%), vascular disease plus autonomic neuropathy in 9/26 (35%), and autonomic neuropathy alone in 6/26 (23%). Many diabetic men complaining of impotence appear to have a significant vascular component which renders intracorporeal papaverine treatment ineffective. We compared the performance of a vacuum constriction-band (Erecaid) and condom-type (Synergist) device in 10 randomly selected men from this group. The devices, provided in random order for 5 months each, were assessed by questionnaire and interview of both the patient and partner. Two couples defaulted and another could use neither device. Although erectile capacity could be restored in the remainder, subsequent intercourse was only deemed satisfactory to both partners in five couples, who unanimously preferred the constriction-band device. In treatment with vacuum devices the constriction-band type seems to be the device of choice; the condom type should probably be reserved for those unable to use the constriction-band type.

Autonomic denervation may be a prerequisite of diabetic neuropathic foot ulceration.

Studies using visceral (cardiovascular) autonomic function testing have left doubt as to the importance of autonomic neuropathy in the development of diabetic neuropathic foot ulceration. A test for peripheral autonomic denervation has been developed (acetylcholine sweatspot test), dependent on intradermal acetylcholine causing secretion by innervated sweat glands, detected by starch/iodine discoloration. The response is photographed and quantified using a grid (normal score = 0 or 1; abnormal = 5 to 60). The sweatspot test was applied to the feet of 19 diabetic patients with a history of foot ulceration, 17 with neuropathic pain, 8 complaining of numbness, and to 15 diabetic control patients. The sweatspot test score of the foot ulcer patients (median 54) was very much greater than that of the other groups (pain group, 4, p less than 0.005; numbness group, 2, p less than 0.01; diabetic control group, 2, p less than 0.0001). All the patients with neuropathic foot ulceration had peripheral autonomic denervation. The results suggest that autonomic denervation in the feet is always present in patients with diabetic neuropathic foot ulceration. Tests of peripheral autonomic denervation such as the acetylcholine sweatspot test may be useful to identify patients at risk of neuropathic foot ulceration.

Clinical outcome and costs of care in radioiodine treatment of hyperthyroidism.

The long-term clinical outcome and costs of treatment of hyperthyroidism with radioiodine have been examined in two cohorts of patients from Sheffield and Scotland. The majority of patients in both series were considered to have Graves' disease. The Sheffield patients (660) were included in a trial of three radioiodine dose regimens of 3,500 (312), 7,000 (323) and 14,000 (25) rad determined using a formula for accurate dosimetry. The Scottish patients (3,920) drawn from five centres in Aberdeen, Dundee, Edinburgh, Glasgow and Inverness were treated using an arbitrary scale, for the activity of radioiodine administered, related to goitre size. Their results are grouped into five MBq 'dose' bands: 37-185, 186-370, 371-555, 556-740 and 741+. The proportion of patients with persistent hyperthyroidism was higher in both cohorts for low-dose radioiodine regimens, but 15-25% of patients who received high doses showed persistent hyperthyroidism. Early and late onset hypothyroidism was lower after low doses but differences between the treatment groups were small in terms of clinical benefit. Total morbidity at 10 years follow-up, in terms of hyperthyroidism, and hypothyroidism, was highest after low-dose therapy. There was little variation in total costs, but patient costs were lowest for the Scottish regimen and highest for low-dose therapy. A dose of at least 370-555 MBq which will ensure early elimination of hyperthyroidism will also limit the medical workload and total costs.

Novel role for specialist nurses in managing diabetes in the community.

To develop care of diabetes further a specialist nurse established contact with general practices in Sheffield Health District and identified difficulties in providing a service for diabetics. One hundred and thirty practices were visited, and full data were collected from 104. Each practice agreed to establish a register of diabetics, and information and support were subsequently provided to help in developing services. In collecting information from each practice the nurse covered specific points on staff, facilities, and organisation. Over two years the service offered in 60 practices considerably improved, allowing a minimum standard of diabetic care to be achieved. This allowed coordinated and effective referral of certain patients from hospital diabetic clinics and improved services to those not attending any clinics.

Ambulatory monitoring of the ST segment in diabetic men with and without peripheral neuropathy.

To assess whether myocardial ischaemia is more common in diabetic patients with neuropathy, 24-hour ambulatory monitoring of the ST segment was performed on 27 diabetic men without peripheral neuropathy and in 28 with neuropathy. The patients were matched for age 54 +/- 7 years (mean +/- SD) versus 54 +/- 7 years and for duration of diabetes (16 +/- 9 years versus 16 +/- 12 years). None had clinical evidence of heart disease. Episodes of ST segment depression were seen during ambulatory monitoring in 12 diabetics (22%) but were not more common in patients with peripheral neuropathy. Four of the 13 diabetics with autonomic neuropathy had ST depression during ambulatory monitoring. During a median follow-up period of 50 months, four patients developed clinical heart disease. Three of these patients had shown ST depression during ambulatory monitoring. ST depression during ambulatory monitoring is common in diabetic men without cardiac symptoms but is not related to the presence of peripheral neuropathy. Diabetics with ST depression during ambulatory monitoring are at increased risk of developing heart disease in subsequent years.

The effect of radioiodine and antithyroid drugs on serum long acting thyroid stimulator protector (IATS-P). A three year prospective study.

Over a three year period we have studied the effect of either a one year course of Carbimazole or a single dose of radioiodine in a group of 46 patients with Graves' disease. Initially, in untreated patients LATS-P was present in 39 (85%) but at the end of the study was only detectable in 19 (41%). The clinical outcome in 29 patients initially treated with carbimazole correlated well with changes in serum LATS-P which persisted in 18. Thirteen of these ultimately required radioiodine or sub-total thyroidectomy. With radioiodine two patterns of response were seen, in some LATS-P levels declined, whereas in others transient increases were seen usually during the first year but subsequently fell. There was no difference in clinical response between the two groups. Overall, the study indicates that serum LATS-P is related to the clinical course of Graves' disease but there remains a minority of patients in whom the activity cannot be detected.

Serum long acting thyroid stimulator (LATS) and LATS-protector (LATS-P) in Graves' disease associated with localized myxedema.

When localized myxedema occurs in Graves' disease, there is often very high serum long acting thyroid stimulator (LATS) activity. However, this association is not invariable and no pathogenetic role for this IgG associated activity is known. Serum LATS protector (LATS-P) is a closely related IgG activity which is present in the majority of cases of untreated Graves' disease. It usually coexists in LATS positive sera in a substantially greater concentration. Its association with localized myxedema has not been studied, nor have serial studies been performed on this activity during the clinical course of the disease. Fourteen patients (13 females, 1 male) with localized myxedema and a history of Graves' disease were examined. In 13 serum LATS was detectable with a wide range of activity from 2.4 to 1,000 units/ml. Serum LATS-P was detected in all including the LATS negative patient with a range of activity from 46 to 4,068 units/ml. Serial studies for at least 2 years were conducted in 8 patients. In two there was no change in either skin lesions or in serum LATS and LATS-P. In 6 the skin lesions partially or completely resolved. In 5 this was associated with statistically significant falls in serum LATS and LATS-P but in one no significant change occurred. The study demonstrated the high prevalence of LATS and LATS-P in localized myxedema. In the sole LATS negative patient there was a high concentration of LATS-P. The role of these activities in the pathogenesis of the disease remains unknown but in serial studies falls in activity were usually associated with clinical improvement.